Topic # 7 (Protein Modification, Aggregation and Degradation in Aging and Age- related Diseases) Cells of older individuals and animals have reduced ability to maintain protein quality control. The resulting accumulation of aberrant proteins is implicated in the pathogenesis of diverse age- dependent "protein aggregation diseases." These degenerative diseases exhibit characteristic "inclusion bodies," which are enriched for aggregates of ubiquitinated, misfolded protein and p62/sequestosome-1, a ubiquitin chainbinding protein that traffics damaged polypeptides to the sequestosome (aggresome) for protein triage. Protein triage in the sequestosome is a precursor to inclusion body formation. An ongoing controversy in the study and treatment of degenerative diseases is whether or not the inclusions bodies with which they are associated are pathogenic, or merely symptoms. We will test the hypothesis that inclusion body formation is in fact, protective, and can delay the progression of disease or stress- induced tissue injury. Preliminary data indicate that 1) cells deficient for p62 cannot form sequestosomes, and 2) genetic ablation of p62 in mice leads to adult-onset obesity and non-alcoholic fatty liver (NAFL), the most prevalent form of liver disease world-wide. With age and chronic oxidative stress resulting from lipid peroxidation, NAFL progresses to steatohepatitis (NASH), which is associated with the formation of p62-enriched Mallory bodies (MBs). We predict that MBs are protective, and that the progression of NAFL to NASH will be accelerated in p62-/- mice due to the inability to form MBs. We will also use a model of oxidation- induced MB formation to demonstrate that expression of a liver-specific p62 transgene restores MB formation and ameliorates liver pathology in young p62-/- mice. Data obtained will be directed to the prevention and treatment of NASH and other age- associated protein aggregation diseases.